Phytochemicals are chemicals produced by plants, and include tannins, lignins, and flavonoids. The largest and best studied polyphenols are the flavonoids, with more than 8,000 identified and classified into at least six subgroups: flavonols, flavones, flavanones, flavanols (and their oligomers, proanthocyanidins), anthocyanidins, and isoflavonoids (Table 1) (USDA Nutrient Data Laboratory. USDA Database for the Flavonoid Content of Selected Foods. (2007) Beltsville, Md.: U.S. Dept. of Agriculture). Only about 100 polyphenols are in foods humans typically eat. Flavonoids are widely distributed in plants and function as plant pigments, signaling molecules, and defenders against infection and injury.
TABLE 1Flavonoid Classification, Examples, and SourcesFlavonoidSubgroupSpecific FlavonoidsFood SourcesFlavonolsQuercetin, kaempferol,onions, apples, leafymyricetin, isorhamnetinvegetables, berriesFlavonesLuteolin, apigeninparsley, hot peppers, celery,artichokes, spicesFlavanonesHesperetin, naringenin,citrus fruits and citrus juiceseriodictyolFlavan-3-olsCatechins,tea, chocolate, tree fruits,epigallocatechins,grape seedtheaflavinsAnthocyanidinsCyaniding, delphinidin,most berries, cowpeasmalvidin, pelargonidin,peonidin, petunidinIsoflavonesDaidzein, genistein,soybeans, soyfoodsglycitein
Dietary intake of flavonoids ranges from 50 to 800 mg/day depending on the consumption of the food source containing various flavonoids. In the U.S., total flavonoid intake averages 251 mg/day (Chun O K, Floegel A, Chung S J, et al. Estimation of antioxidant intakes from diet and supplements in U.S. adults. J Nutr 2010; 140:317-24; the disclosure of which is incorporated by reference herein in its entirety), and in Spain 313 mg/day (Zamora-Ros R, Andres-Lacueva C, Lamuela-Raventós R M, et al. Estimation of dietary sources and flavonoid intake in a Spanish adult population (EPIC-Spain). J Am Diet Assoc 2010; 110:390-8; the disclosure of which is incorporated by reference herein in its entirety), with important sources including tea, citrus fruit and juice, beers and ales, wines, melon and berries, apples, onions, and bananas. Only about 29% of individuals consume tea on a given day, and without tea consumption, the flavonoid intake is closer to about 50 mg/day, reflecting the low intake of fruits and vegetables by U.S. adults. The typical American is a low consumer of fruit (0.53 cups/1000 calories) and vegetables (0.77 cups/1000 calories), well below the Healthy People 2020 goals of 0.90 cups/1000 calories for fruit and 1.14 cups/1000 calories for vegetables.
A high intake of fruits and vegetables has been linked in numerous studies to reduced risk of cardiovascular disease and various types of cancer. The disease-reducing influence of fruits and vegetables may be due in part to high levels of flavonoids (Hooper L, Kroon P A, Rimm E B, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88:38-50; Wang L, Lee I M, Zhang S M, et al. Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am J Clin Nutr 2009; 89:905-12; Zamora-Ros R1, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, Andres-Lacueva C. High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults. J Nutr. 2013; 143:1445-50). A 12-year study of 807 elderly men and women in Italy showed that those in the upper tertile for total urinary polyphenol concentration (a proxy measure of fruit and vegetable intake) experienced a 30% reduction in all-cause mortality (Zamora-Ros R1, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, Andres-Lacueva C. High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults. J Nutr. 2013; 143:1445-50). These data strongly support that a high polyphenol intake is associated with extended longevity.
Many flavonoids possess strong anti-inflammatory, anti-viral, antioxidant, anti-obesity, and anti-carcinogenic properties when studied in vitro using large doses of the purified form. Inflammation and oxidative stress are key mechanisms in the pathogenesis of certain disease states, supporting the proposed strategy of increased flavonoid intake for prevention of cancer, diabetes mellitus, and cardiovascular disease. However, results from randomized, double-blinded studies in humans with large doses of purified flavonoids such as quercetin have been disappointing (Shanely R A, Knab A M, Nieman D C, et al. Quercetin supplementation does not alter antioxidant status in humans. Free Radic Res 2010; 44:224-31). Flavonoids vary widely in bioavailability, and most are poorly absorbed, undergo active efflux, and are extensively conjugated and metabolically transformed, all of which can affect their bioactive capacities (Zhang L, Zuo Z, Lin G. Intestinal and hepatic glucuronidation of flavonoids. Mol Pharm 2007; 4:833-45). Despite low bioavailability of the parent flavonoid, some of the in vivo metabolites may accumulate in tissues and produce bioactive influences, but conclusive human data are lacking. For example, animal data indicate that quercetin metabolites accumulate in the vascular tissue and there act as complementary antioxidants, with plasma albumin facilitating the translocation of quercetin metabolites to the vascular target (Terao J, Kawai Y, Murota K. Vegetable flavonoids and cardiovascular disease. Asia Pac J Clin Nutr 2008; 17(Suppl 1): 291-3).
There is a growing realization that bioactive influences of individual flavonoids are potentiated when mixed with other flavonoids (for example, the flavonol quercetin with the flavanol epigallocatechin 3-gallate (EGCG)) or included in a cocktail or extract of other polyphenols and nutrients (Lila M A. From beans to berries and beyond: teamwork between plant chemicals for protection of optimal human health. Ann N Y Acad Sci 2007; 1114:372-80). Two or more flavonoids ingested together may increase bioavailability and decrease elimination via competitive inhibition of glucuronide and sulfate conjugation in both the intestine and liver, and by inhibiting efflux transporters such as P-glycoprotein, breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) (Kale A, Gawande S, Kotwal S, et al. Studies on the effects of oral administration of nutrient mixture, quercetin and red onions on the bioavailability of epigallocatechin gallate from green tea extract. Phytother Res 2010; 24 (Suppl 1):S48-55).
The health-protective effects of plant foods are not produced by a single component but rather complex mixtures of interacting molecules (Lila M A. From beans to berries and beyond: teamwork between plant chemicals for protection of optimal human health. Ann N Y Acad Sci 2007; 1114:372-80). The polyphenols and natural components provide a multifaceted defensive strategy for both plants and humans. Thus the “pharma” approach of using large doses of a single bioactive molecule is seldom successful in the application of nutrition to human health and performance. Additionally, a metabolomics or nutrigenomics approach is needed to improve the capacity of investigators to capture the complex and subtle influences of flavonoid supplements or flavonoid-rich extracts, foods, and beverages on whole-body metabolism and physiology (Bakker G C, van Erk M J, Pellis L, et al. An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 2010; 91:1044-59).
Quercetin is a flavonol compound that is found in many fruits and vegetables, such as red onions, capers, black plums, blueberries, and red applies. It has been reported to provide numerous health benefits to humans that ingest the compound. These reported health benefits include acting as a powerful antioxidant, improving athletic performance, improving cardiovascular health, and aiding in immune response. Some studies have found that quercetin can reduce blood pressure and LDL cholesterol. Other studies have found that quercetin can increase athletic performance.
Although quercetin can provide numerous benefits, many people may not be able to fully realize its benefits. For example, for many people there may not be a convenient source of quercetin available to them. In some cases, some people may not enjoy the taste and/or flavors of natural sources of quercetin. In other instances, some people may not be able to consume sufficient amounts of quercetin to receive a beneficial effect. In other cases, some people may not be able to consume quercetin in a manner that makes the quercetin bioavailable.
Therefore, challenges currently exist in realizing the benefits of quercetin. Accordingly, it would be an improvement in the art to provide compositions and methods to more fully realize the benefits of quercetin.